The long-term goal of this research program is to examine the relationship between hormone levels, circadian function and behavior. The central aim of this proposal is to determine if hormones regulate the activity of the biological clock. In particular, we have focused on estrogen regulation of cells in the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) of the lateral geniculate body and their effects on circadian gonadotropin release. Our preliminary data revealed that subdivisions of the SCN and IGL of the lateral geniculate body are targets of gonadal steroid action during development and adulthood. We propose that disruption of these circuits by hormonal manipulation during development and/or adulthood interfere with the emergence and/or maintenance of the circadian positive gonadotropin feedback. To test this hypothesis we will address the following Specific Aims: 1) To reveal the interaction between gonadal steroid receptors and neuronal populations of the SCN and IGL. In this regard, a) determine if during perinatal development, neurons that express estrogen receptors contain estrogen synthetase, aromatase, b) reveal whether sexual dimorphism emerge in aromatase activity of the SCN and IGL; and c) in adult animals demonstrate whether estrogen- and/or progesterone receptor-containing neurons give rise to projections to hypothalamic regions where neuroendocrine cells are located. 2) To demonstrate whether the observed sex difference in the input of the neuroendocrine cells that arises from the biological clock is due to developmental effects of estradiol or is the consequence of the effects of gonadal steroids in adulthood. 3) To assess the effects of hormonal manipulations of the SCN and/or the IGL during adulthood on the gender specific gonadotropin secretion and the expression of GAD65 and GAD67 mRNAs in the SCN and IGL. The proposed experiments will elucidate a novel mechanism to support hormone-dependent endocrine mechanisms. Furthermore, our results revealing mechanisms via which hormonal signals can regulate components of the biological clock can provide a new insight into the etiology of discomforting symptoms of gonadal failure, including mood swings, sleep disorders and disturbances in thermoregulation (hot flushes), all of which are tightly coupled to the activity of the biological clock.